Interaction between docetaxel resistance and castration resistance in prostate cancer: Implications of Twist1, YB-1, and androgen receptor
Interaction between docetaxel resistance and castration resistance in prostate cancer: Implications of Twist1, YB-1, and androgen receptor
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DOI：
10.1002/pros.22681
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发表时间：
2013-09-01
期刊：
影响因子：
2.8
通讯作者：
Naito, Seiji
中科院分区：
文献类型：
--
作者：
Shiota, Masaki;Kashiwagi, Eiji;Naito, Seiji
背景紫杉烷类药物（包括多西他赛）是目前唯一被证明可为去势抵抗性前列腺癌（CRPC）患者提供生存获益的细胞毒性化疗药物。然而，紫杉烷类的优点仍然有限，需要努力提高其治疗效果。我们使用细胞毒性试验评估了前列腺癌细胞对各种药物的敏感性。基因和蛋白质表达水平进行了评估，分别通过定量实时聚合酶链反应和蛋白质印迹分析。过表达Twist 1和Y-box结合蛋白-1（YB-1）的抗过氧化氢和抗阉割细胞对包括多西他赛在内的细胞毒性药物具有交叉耐药性。Twist 1调节YB-1在前列腺癌细胞中的表达，通过转化生长因子对Twist 1和YB-1的诱导来支持，这对紫杉烷耐药至关重要。Twist 1和/或YB-1在紫杉醇耐药的前列腺癌细胞中被激活，并且YB-1被多西他赛处理激活。相反，Twist 1和YB-1敲低使前列腺癌细胞对细胞毒性剂（包括多西他赛）敏感。此外，雄激素受体（AR）敲除增加细胞对多西他赛的敏感性，虽然AR在多西他赛耐药LNCaP细胞中的表达自相矛盾地低于亲本细胞。有趣的是，雄激素剥夺治疗在紫杉醇耐药的LNCaP细胞中比亲本细胞更有效。Twist 1/YB-1和AR信号通路促进CRPC细胞对多西他赛的耐药性然而，紫杉醇耐药细胞对雄激素剥夺是间接敏感的，因为AR表达下调，这表明在CRPC中，初始紫杉烷治疗对初次接受紫杉烷治疗的前列腺癌的治疗效果可能上级补救性紫杉烷治疗。前列腺73：1336-1344，2013年。(c)2013 Wiley Periodicals，Inc.
BACKGROUND. Taxanes, including docetaxel, are currently the only cytotoxic chemotherapeutic agents proven to confer survival benefit in patients with castration-resistant prostate cancer (CRPC). However, the merits of taxanes remain modest, and efforts are needed to improve their therapeutic efficacy.METHODS. We evaluated the sensitivity of prostate cancer cells to various agents using cytotoxicity assays. Gene and protein expression levels were evaluated by quantitative real-time polymerase chain reaction and Western blotting analysis, respectively.RESULTS. Hydrogen peroxide-resistant and castration-resistant cells that overexpressed Twist1 and Y-box binding protein-1 (YB-1) were cross-resistant to cytotoxic agents, including docetaxel. Twist1 regulated YB-1 expression in prostate cancer cells, supported by the induction of Twist1 and YB-1 by transforming-growth factor-, which is critical for taxane resistance. Twist1 and/or YB-1 were activated in docetaxel-resistant prostate cancer cells, and YB-1 was activated by docetaxel treatment. Conversely, Twist1 and YB-1 knockdown sensitized prostate cancer cells to cytotoxic agents, including docetaxel. In addition, androgen receptor (AR) knockdown increased cellular sensitivity to docetaxel, though AR expression in docetaxel-resistant LNCaP cells was paradoxically lower than in parental cells. Intriguingly, androgen deprivation treatment was more effective in docetaxel-resistant LNCaP cells compared with parental cells.CONCLUSIONS. Twist1/YB-1 and AR signaling promote docetaxel resistance in CRPC cells. However, docetaxel-resistant cells were collaterally sensitive to androgen deprivation because of down-regulation of AR expression, suggesting that the therapeutic effect of initial taxane treatment in hormone-naive prostate cancer may be superior to that of salvage taxane treatment in CRPC. Prostate 73: 1336-1344, 2013. (c) 2013 Wiley Periodicals, Inc.